Tofacitinib for rheumatoid arthritis

  • Protocol
  • Intervention

Authors

  • Maria Angeles Lopez-Olivo,

    Corresponding author
    1. The University of Texas, M.D. Anderson Cancer Center, Department of General Internal Medicine, Houston, Texas, USA
    • Maria Angeles Lopez-Olivo, Department of General Internal Medicine, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1465, Houston, Texas, 77030, USA. amlopezo@mdanderson.org.

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  • Mahesh Bavineni,

    1. The University of Texas, M.D. Anderson Cancer Center, Department of General Internal Medicine, Houston, Texas, USA
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  • Maria E Suarez-Almazor

    1. The University of Texas, M.D. Anderson Cancer Center, Department of General Internal Medicine, Houston, Texas, USA
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Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To evaluate the benefits and harms of tofacitinib for the treatment of rheumatoid arthritis.

Our PICO question is as follows:

Population: Adult patients with rheumatoid arthritis.

Intervention: Tofacitinib alone or combined with any DMARD.

Comparison: Placebo or DMARD.

Outcomes: Efficacy, radiographic, patient-reported and safety outcomes.

Background

Description of the condition

Rheumatoid arthritis is a chronic systemic inflammatory disorder primarily affecting the synovial membrane. This inflammatory process leads to painful swelling of the joints due to the excess production of synovial fluid and fibrous tissue formation, which eventually results in bone erosion and joint deformity (Kvien 2005). Rheumatoid arthritis affects around 1% of the population in the world and it affects women more commonly than men in the age group of 40 to 60 years old (Silman 1998). Goals of the treatment are to reduce the disease activity, improve physical function, improve health-related quality of life, and to inhibit progression of structural damage throughout the course of the disease (Fries 1996). Treatment is primarily focused on disease modifying anti-rheumatic drugs (DMARDs), which are administered either orally, intravenously or by injection.

Description of the intervention

Tofacitinib was developed as a small molecule inhibitor of the Janus kinase (JAK) pathways that are central to the maintenance of the inflammatory state in rheumatoid arthritis (Regens 2011). The JAK family of kinases play a key role in cytokine induced signal transduction. Tofacitinib is highly specific for the JAK family of kinases over the other kinases. By inhibiting the activity of JAKs, tofacitinib reduces the production and modulates the effects of the key pro-inflammatory cytokines whose dysregulation is critical to immune cell activation, pro-inflammatory cytokine production and cytokine signalling. Tofacitinib is orally administered, usually in the dose range of 5 mg to 15 mg twice a day and has a half-life of two to five hours (Yamaoka 2012). The most common adverse effects are headache, nausea, and elevations in transaminase and creatinine levels (Fleischmann 2012). In a dose-dependent manner it increases the total cholesterol, high- and low-density lipoprotein levels and causes anemia and neutropenia in patients treated with doses of 30 mg twice a day; which suggest that this drug acts on the hematopoietic system through the pathway of JAK-2 inhibition (Zerbini 2012).

How the intervention might work

Tofacitinib selectively inhibits JAK-1, JAK-2 and JAK-3 in vitro, reducing the production of key pro-inflammatory cytokines which play a central role in the pathology of rheumatoid arthritis (Tanaka 2012). In recent randomized controlled trials, tofacitinib demonstrated rapid, significant, and clinically meaningful reductions in the disease activity score and improvements in physical function (Coombs 2010).

Why it is important to do this review

Although multiple DMARDs are available to treat rheumatoid arthritis, and combination therapy is frequently employed, many patients remain inadequately treated and continue to suffer pain, disability and progressive joint damage. Up to one third of patients do not adequately respond and about half stop responding to any particular DMARD within five years (Saag 2008). Since 1998, nine biologic agents have been approved by the US Food and Drug Administration (FDA) to treat moderate to severe rheumatoid arthritis that has not responded to an adequate trial of one or more of the traditional DMARDs. However, biologic DMARDs are expensive and due to the duration and chronic nature of the disease, patients can expect to require treatment for up to 40 years over their lifetime. A high likelihood that a patient will stop responding to any particular therapy means that many patients will exhaust available treatment options during the course of their disease. Thus, exploring additional therapeutic options with different mechanisms of action remains necessary to treat patients with moderate to severe disease. Tofacitinib is a targeted immune modulator that is being investigated for patients with rheumatoid arthritis. Compared with the newer therapeutic options, tofacitinib may have two advantages: (i) it can be orally administered and (ii) it is less costly (Bonilla-Hernan 2011). In this review, we will summarize the available evidence on the benefits and harms of tofacitinib. A systematic review may help clinicians in the decision-making process and in the implementation of the evidence into clinical practice.

Objectives

To evaluate the benefits and harms of tofacitinib for the treatment of rheumatoid arthritis.

Our PICO question is as follows:

Population: Adult patients with rheumatoid arthritis.

Intervention: Tofacitinib alone or combined with any DMARD.

Comparison: Placebo or DMARD.

Outcomes: Efficacy, radiographic, patient-reported and safety outcomes.

Methods

Criteria for considering studies for this review

Types of studies

We will include any randomized controlled trial (RCT) or controlled clinical trial (CCT) comparing tofacitinib alone or in combination with any DMARD versus placebo or other traditional or biologic DMARDs. We will also include open label studies (OLTs). We will consider data from published and unpublished studies for inclusion.

Types of participants

Patients at least 16 years of age meeting the American College of Rheumatology 1987 revised criteria for rheumatoid arthritis (Arnett 1988) and having active disease as described by authors in relation to the outcome measures.

Types of interventions

Treatment with tofacitinib alone or in combination with any DMARD compared with placebo or other traditional or biologic DMARDs will be eligible for inclusion. We will consider for primary analysis the doses of 5 mg and 10 mg (twice a day). Secondary analyses will include all other doses.

Types of outcome measures

Major outcomes

The major outcomes included in this review will be the response of rheumatoid arthritis to treatment with tofacitinib as defined by the World Health Organization (WHO), the International League of Associations for Rheumatology (ILAR) core set of disease activity measures for rheumatoid arthritis clinical trials and the adverse effects of the drug.

1) American College of Rheumatology (ACR) improvement criteria (Felson 1995) which is defined as an improvement in response rates of 20%, 50% or 70% in tender and swollen joints, in addition to a 20%, 50% or 70% improvement observed in 3 out of 5 in core measures like patient and physical global assessments, pain, functional status and an acute phase reactant.

2) European League against Rheumatism (EULAR) improvement criteria which include a change in the disease activity in addition to activity of the current disease. According to EULAR, patients are classified as responders if there is a change in disease activity score (DAS) and low current disease activity is observed. It includes three categories: good, moderate, and non-responders (van Gestel 1996).

3) Radiographic scores, to detect a change in the score from baseline, which include:

i) Total Sharp Score (TSS) with score range 0 to 448;

ii) Erosion Scores (ES)

iii) Joint Space Narrowing Score (JSNS)

Scores for ES and JSNS are summed to yield the TSS (van der Heijde 1999).

4) Remission rates which are considered as a useful measure of the disease activity measured in the range of either a DAS < 1.6 or < 2.6 (Prevoo 1995) or ACR/EULAR 2011 remission definition, either Boolean (Total joint count (TJC) ≤ 1, swollen joint count (SJC) ≤ 1, C-reactive protein (CRP) ≤ 1 mg/dL, patient global assessment ≤ 1) or index-based (Simplified Disease Activity Index ≤ 3.3) (Felson 2011).

5) Safety outcomes: A) Adverse events including: i) total, ii) common (allergic reactions, headache, nausea), iii) expected (alterations in the cholesterol levels, decrease in hemoglobin, increase in creatinine, elevations of transaminase levels, decrease in the neutrophils), iv) infections (including herpes zoster (shingles)), (v) serious (gastrointestinal perforations) and deaths; and B) Withdrawals: total, due to lack of efficacy, and due to adverse events.

Minor outcomes

The included minor outcomes will be:

1. Generic health-related quality of life (HRQOL) indices such as the SF-36 (Fries 1980).

2. Patient assessment of functional ability such as Health Assessment Questionnaire (HAQ) (Fries 1980) and Arthritis Impact Measurement Scale (AIMS) (Meenan 1980).

Summary of Findings tables will include the following outcomes: ACR50, DAS (low or remission), HAQ for function, X-ray or appropriate imaging changes, short term serious adverse effects from trials, HRQOL, discontinuation rates.

Search methods for identification of studies

Electronic searches

We will search for published data in the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, Web of Science, International Pharmaceutical Abstracts (IPA) database and Biological abstracts (Dickersin 1994). The specific search strategy will be constructed according to the Cochrane Musculoskeletal Group methods used in reviews (Appendix 1).

Searching other resources

We will also search clinical trials.gov, the ADIS Clinical Trials database and handsearch the list of references of potentially relevant citations which were not published or otherwise found. Additionally, we will attempt to contact the authors of included studies and the tofacitinib manufacturer (Pfizer) for any additional information that has not been published, or when trial data are unclear, or further details are needed.

Data collection and analysis

EndNote X5 software will be used to manage the records retrieved from searches of electronic databases. Results from other resources will be kept on a Microsoft Excel spreadsheet.

Selection of studies

Two review authors will screen all of the unique citations obtained by the electronic search strategy and other sources. We will resolve any disagreement through discussion and consensus. If no consensus is reached, a third party will act as an adjudicator.

Data extraction and management

The data will be extracted independently by two authors and will be cross-checked for any errors; any discrepancies will be resolved by discussion.

Data from each included trial will be extracted in a pre-designed Word form to capture the following information (when available):

1. General study information: title, authors, country, follow-up, year, funding agency, study design, setting, risk of bias, number of patients randomized, number of patients analyzed.

2. Characteristics of participants: age, sex, disease duration, concurrent treatments.

3. Characteristics of intervention: dosages, methods of administration, frequency, duration of treatment, withdrawals, drop-outs.

4. Characteristics of control: active or placebo; if active, then drug name, dosages, methods of administration, frequency, duration of treatment, withdrawals, drop-outs.

5. Outcome variables: all outcomes assessed by the authors.

Assessment of risk of bias in included studies

Two authors will independently assess the risk of bias. We will follow The Cochrane Collaboration's recommendations for assessment. In a consensus meeting disagreements among the authors will be discussed and resolved. If disagreement persists, a final decision will be facilitated by a third author. We will summarize the risk of bias assessment for every outcome included in the summary of findings tables within a study. Studies will be appraised for selection bias, performance bias, detection bias, attrition bias, reporting bias, and other biases (i.e. baseline imbalance and funding). We will explore these biases judging the following criteria: adequate sequence generation, allocation concealment, blinding of participants (for all key outcomes: ACR50, DAS, radiographic progression), personnel and outcome assessors, incomplete outcome data (for all key outcomes: ACR50, withdrawals, AEs), free of selective reporting and other biases (Higgins 2011). We will grade each potential source of bias as low, unclear, or high, and will provide a quote from the study report and justification for each judgement in the risk of bias table. The final ratings for all included studies will be presented in a ‘risk of bias’ summary figure.

Measures of treatment effect

For efficacy outcomes, we will analyze data as reported in the studies (either modified intention-to-treat, per protocol, or treatment-received analysis). For dichotomous variables, we will determine the risk ratio (RR) or Peto odds ratios (Peto OR) in the case of rare events (< 10%). Continuous data will be measured by using mean difference or standardized mean difference to compare same outcomes measured with different scales and 95% confidence intervals (CI) will be estimated for all measures of treatment effect. For safety outcomes, an intention-to-treat model will be used to analyze the data. We will report the risk ratio and its 95% CI for the number of patients with adverse events and number of discontinuations, and Peto OR and its 95% CI for the number of patients who developed malignancies and deaths. Studies reporting only events (not subjects) will be presented in a table with no attempt to summarize the data.

Unit of analysis issues

Treatment groups will be analyzed separately (for trials comparing more than two dosages of tofacitinib). Analysis of outcomes will be performed at 12, 24 and 52 weeks. We will include the following comparison groups: (i) tofacitinib vs placebo; (ii) tofacitinib + methotrexate vs placebo + methotrexate; (iii) tofacitinib vs adalimumab; (iv) tofacitinib + methotrexate vs tofacitinib monotherapy.

Dealing with missing data

For continuous data, the mean and standard deviation (SD) will be used when available. Missing SDs will be calculated from other statistics such as standard errors, confidence intervals or P value, according to the methods recommended in the Cochrane Handbook for Systematic Reviews of Interventions. If SD is not provided at any follow-up visit, we will use the baseline SD. In cases where only the median and interquartile ranges (or minimum and maximum values) are reported, the median will be used as the mean, and one half of the difference between the 1st and 3rd quartile range will be used as the SD (Higgins 2011). Data provided in graphs only will also be extracted.

Assessment of heterogeneity

All outcomes will be analyzed using a fixed-effect model. However, a random-effects model will be used when heterogeneity is present. Data will not be pooled if significant heterogeneity exists. The reasons for heterogeneity will be explored through subgroup analysis. Heterogeneity of the data will be calculated using the Chi2 test using n-1 degrees for freedom and a P value less than or equal to 0.10. We will use the I2 statistic to describe the percentage of the variability in effect estimates that is due to heterogeneity rather than chance. Values ranging from 0% to 40% have been considered as not important; 30% to 60% is considered to represent moderate heterogeneity; 50% to 90% may represent substantial heterogeneity; and 75% to 100% considerable heterogeneity (Higgins 2011).

Assessment of reporting biases

Publication bias will be explored with inverted funnel plots. In the absence of bias, the plot will resemble a symmetrical, inverted funnel; if there is bias, it will lead to an asymmetrical appearance of the funnel plot. The more pronounced the asymmetry, the more likely it is that the amount of bias will be substantial. Even if insufficient trials are identified to interpret a funnel plot appropriately, studies will be appraised individually for reporting bias (i.e. publication, time-lag, multiple publication, location, citation, language and selective reporting).

Data synthesis

The results of the studies will be analyzed using Review Manager Version 5.2. We will summarize the data of clinically homogeneous studies in a meta-analysis. A random-effects model will be used when heterogeneity is present. Data will not be pooled if significant heterogeneity exists.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis will be conducted to determine the effects of disease duration (< 2 years vs ≥ 2 years), previous DMARD treatment (DMARD-naive vs prior DMARD exposure vs prior biologic DMARD exposure), and geographic region (e.g. Asia vs US/Western Europe). Subgroup analyses will be restricted to the ACR improvement criteria of 50%. Clinical heterogeneity will also be explored by grouping trials with true inactive controls vs methotrexate add-on trials vs biologics as controls.

Sensitivity analysis

If sufficient trials are identified, we plan to conduct a sensitivity analysis comparing the results using all trials with high methodological quality: studies classified as having a 'low risk of bias' versus those identified as having a 'high risk of bias' in allocation concealment and blinding for the ACR improvement criteria of 50% (Higgins 2011).

Summary of findings tables

Summary of findings tables will include the absolute and relative magnitude of effect, and the number needed to treat for an additional beneficial outcome (NNTB) and their 95% confidence intervals. The NNTB will be calculated with the Visual Rx NNTB calculator (Cates 2008). For continuous outcomes, the NNTB calculation will be requested from the Cochrane Musculoskeletal Group editorial office. We will use the GRADE Working Group grades of evidence (Guyatt 2008) in the 'Summary of findings' table. The evidence will be graded as follows:
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Acknowledgements

We would like to thank Gregory F. Pratt, DDS, MS, at the Research Medical Library of The University of Texas M.D. Anderson Cancer Center, for providing comments on the 'search methods for identification of studies' section.

Appendices

Appendix 1. Appendix: Search Strategy

MEDLINE

1. tofacitinib.mp.

2. tasocitinib.mp.

3. cp690550.mp.

4. "cp 690550".mp.

5. "cp 690 550".mp.

6. or/1-5

7. exp Arthritis, Rheumatoid/

8. (rheumatoid adj5 arthrit*).mp.

9. (stills or still's or felty* or sjogren* or sicca* or sjoegren* or vasculit* or arthrit* or caplan*).mp.

10. or/7-9

11. 6 and 10

EMBASE

1. tofacitinib.mp.

2. tasocitinib.mp.

3. cp690550.mp.

4. "cp 690550".mp.

5. "cp 690 550".mp.

6. or/1-5

7. exp Arthritis, Rheumatoid/

8. (rheumatoid adj5 arthrit*).mp.

9. (stills or still's or felty* or sjogren* or sicca* or sjoegren* or vasculit* or arthrit* or caplan*).mp.

10. or/7-9

11. 6 and 10

WEB OF SCIENCE

1. TS= (tofacitinib or tasocitinib or cp690550 or "cp-690550" or "cp 690550" or "cp-690,550" or "cp 690,550" or "cp-690 550" or "cp 690 550")

2. TS= (rheumat* NEAR/5 arthrit*)

3. TS= (stills or still's or felty* or sjogren* or sicca* or sjoegren* or vasculit* or arthrit* or caplan*)

4. 2 OR 3

5. 1 AND 4

CENTRAL

1. (tofacitinib OR tasocitinib) in Trials

2. (cp690550 or "cp-690550" or "cp 690550" or "cp-690,550" or "cp 690,550" or "cp-690 550" or "cp 690 550") in Trials

3. (1 OR 2)

4. (rheumat* NEAR/5 arthrit*) in Trials

5. MeSH descriptor Arthritis, Rheumatoid explode all trees

6. (stills or still's or felty* or sjogren* or sicca* or sjoegren* or vasculit* or arthrit* or caplan*) in Trials

7. (4 OR 5 OR 6)

8. (3 AND 7)

CINAHL

1. tofacitinib or tasocitinib

2. cp690550 or "cp-690550" or "cp 690550" or "cp-690,550" or "cp 690,550" or "cp-690 550" or "cp 690 550"

3. S1 or S2

4. (MH "Arthritis, Rheumatoid+")

5. (rheumat* N5 arthrit*)

6. stills or still's or felty* or sjogren* or sicca* or sjoegren* or vasculit* or arthrit* or caplan*

7. S4 or S5 or S6

8. S3 and S7

BIOLOGICAL ABSTRACTS

1. (tofacitinib or tasocitinib).mp.

2. (cp690550 or "cp-690550" or "cp 690550" or "cp-690,550" or "cp 690,550" or "cp-690 550" or "cp 690 550").mp.

3. 1 or 2

4. (rheumat* adj5 arthrit*).mp.

5. (stills or still's or felty* or sjogren* or sicca* or sjoegren* or vasculit* or arthrit* or caplan*).mp.

6. 4 or 5

7. 3 and 6

INTERNATIONAL PHARMACEUTICAL ABSTRACTS

1. (tofacitinib or tasocitinib or cp690550 or "cp-690550" or "cp 690550" or "cp-690,550" or "cp 690,550" or "cp-690 550" or "cp 690 550").mp.

2. (rheumat* adj5 arthrit*).mp.

3. (stills or still's or felty* or sjogren* or sicca* or sjoegren* or vasculit* or arthrit* or caplan*).mp.

4. 1 and (2 or 3)

CLINICAL TRIALS.gov

1. (tofacitinib OR tasocitinib OR cp690550 OR cp-690550 OR cp-690,550) And rheumatoid arthritis

Contributions of authors

Draft protocol - Mahesh B, Lopez-Olivo MA, Suarez-Almazor ME

Search strategy - Pratt G

Identify relevant titles and abstracts from searches - Mahesh B, Lopez-Olivo MA

Obtain copies of trials - Mahesh B

Selection of trials - Mahesh B, Lopez-Olivo MA, Suarez-Almazor ME

Extract data from trials - Mahesh B, Lopez-Olivo MA

Enter data into RevMan - Mahesh B

Carry out analysis - Mahesh B, Lopez-Olivo MA

Interpret data - Mahesh B, Lopez-Olivo MA, Suarez-Almazor ME

Draft final review - Mahesh B, Lopez-Olivo MA, Suarez-Almazor ME

Update review - Mahesh B, Lopez-Olivo MA, Suarez-Almazor ME

Declarations of interest

None known.

Sources of support

Internal sources

  • The University of Texas MD Anderson Cancer Center, USA.

External sources

  • No sources of support supplied

Ancillary